Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

Eur J Hum Genet. 2018 Feb;26(2):210-219. doi: 10.1038/s41431-017-0010-5.

Anneke Kievit ¹, Federico Tessadori ² ³, Hannie Douben ⁴, Ingrid Jordens ², Madelon Maurice ², Jeannette Hoogeboom ⁴, Raoul Hennekam ⁵, Sheela Nampoothiri ⁶, Hülya Kayserili ⁷, Marco Castori ⁸, Margo Whiteford ⁹, Connie Motter ¹⁰, Catherine Melver ¹⁰, Michael Cunningham ¹¹, Anne Hing ¹¹, Nancy M Kokitsu-Nakata ¹², Siulan Vendramini-Pittoli ¹², Antonio Richieri-Costa ¹², Annette F Baas ², Corstiaan C Breugem ¹³, Karen Duran ², Maarten Massink ², Patrick W B Derksen ¹⁴, Wilfred F J van IJcken ¹⁵, Leontine van Unen ⁴, Fernando Santos-Simarro ¹⁶, Pablo Lapunzina ¹⁶, Vera L Gil-da Silva Lopes ¹⁷, Elaine Lustosa-Mendes ¹⁷, Max Krall ¹⁸, Anne Slavotinek ¹⁸, Victor Martinez-Glez ¹⁶, Jeroen Bakkers ³ ¹⁹, Koen L I van Gassen ², Annelies de Klein ⁴, Marie-José H van den Boogaard ², Gijs van Haaften ²⁰

Affiliations

1 Department of Clinical Genetics, Erasmus Medical Center Rotterdam, Rotterdam, 3015CN, The Netherlands. [email protected].
2 Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584CG, The Netherlands.
3 Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, 3584CT, The Netherlands.
4 Department of Clinical Genetics, Erasmus Medical Center Rotterdam, Rotterdam, 3015CN, The Netherlands.
5 Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, 1105AZ, The Netherlands.
6 Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kerala, 682041, India.
7 Department of Medical Genetics, Koç University School of Medicine, Istanbul, 34450, Turkey.
8 Division of Medical Genetics, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, 71013, Italy.
9 Department of Clinical Genetics, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK.
10 Division of Medical Genetics, Akron Children's Hospital, Akron, OH, 44308, USA.
11 Division of Craniofacial Medicine, University of Washington Department of Pediatrics, Jean Renny Chair of Craniofacial Medicine, Seattle Children's Craniofacial Center, Seattle, WA, 98105, USA.
12 Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of São Paulo, Bauru, 17012-900, Brazil.
13 Department of Pediatric Plastic Surgery, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, 3584EA, The Netherlands.
14 Department of Pathology, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
15 Erasmus Center for Biomics, Erasmus Medical Center, Rotterdam, 3015CN, The Netherlands.
16 INGEMM, Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, CIBERER, ISCIII, Madrid, 28049, Spain.
17 Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, UNICAMP, Campinas, São Paulo, 13083-970, Brazil.
18 Department of Pediatrics, University of California, San Francisco, Benioff Children's Hospital, San Francisco, CA, 94158, USA.
19 Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, 3584CM, The Netherlands.
20 Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584CG, The Netherlands. [email protected].

PMID: 29348693 DOI: 10.1038/s41431-017-0010-5

Abstract

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric Cancer and invasive lobular breast cancer; however, no cases of gastric or breast Cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

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